Craniofacial anomalies are common birth defects, especially those associated with orofacial clefts. It is apparent that genetic factors contribute significantly to their etiology. However, genes for many craniofacial anomalies have not been identified. Most orofacial clefts are non-syndromic, isolated defects, which can be separated into two different phenotypes: cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO). Both are genetically complex traits, which has limited the ability to identify disease loci or genes. Efforts to identify genes for non-syndromic clefts have relied on candidate gene approaches. However, mutations have not been identified for either non-syndromic CL/P or CPO. The overall objective of this and future projects is to identify disease loci and genes involved in non-syndromic CL/P and CPO. This can be accomplished by employing several approaches, included focused research on non-syndromic clefts. In addition, identifying genes for syndromic clefts, which have simple Mendelian inheritance patterns, may also provide clues to the etiology of non-syndromic clefts. The specific aim of this project is to ascertain large inbred families with non-syndromic CL/P and CPO from Jordan. However, during this process it is likely that large, in bred families with other craniofacial anomalies will also be identified. Therefore, these families will also be recruited. An important ramification of inbreeding is that in a family, individuals with a rare recessive disease are likely to have inherited both copies of the mutated gene from a common ancestor; i.e., identical by descent. This fact facilitates gene locus identification by a DNA pooling approach to homozygosity mapping. This approach has been used to identify disease loci in families with as few as 5 affected members. Once a disease locus is identified, formal linkage analysis with nearby markers will be performed using a program, Genehunter, to confirm the results. Genehunter is specifically designed for inbred families. In addition, nearby candidate genes will be screened for mutations. It is anticipated that 2-3 large families will be recruited per year. Already a large family with frontonasal dysplasia has been identified. In addition, individuals with non-syndromic CL/P or CPO who are from inbred families will also be recruited for linkage analysis. The population available for identifying subjects is projected to have 50 non- syndromic CL/P and 25 non-syndromic CPO newborns from inbred marriage per year. The population of Jordan is unique in that consanguineous marriages comprise over 50% of all marriages. This project presents the opportunity to rapidly identify disease loci for non-syndromic CL/P and CPO as well as other craniofacial anomalies by the use of a novel, efficient homozygosity mapping strategy. Finally, the recruitment of small inbred families with non-syndromic CL/P and CPO will provide a foundation for future genome scans for disease loci.